1-3--diethyl-4-2--quinolylthiacyanine-iodide and Neoplasms

Active targeting uses molecular fragments that bind receptors overexpressed on cell surfaces to deliver cargoes, and this selective delivery to diseased over healthy tissue is valuable in diagnostic imaging and therapy. For instance, targeted near-infrared (near-IR) dyes can mark tissue to be excised in surgery, and radiologists can use active targeting to concentrate agents for positron emission tomography (PET) in tumor tissue to monitor tumor metastases. Selective delivery to diseased tissue is also valuable in some treatments wherein therapeutic indexes (toxic/effective doses) are key determinants of efficacy. However, active targeting will only work for cells expressing the pivotal cell surface receptor that is targeted. That is a problem because tumors, even ones derived from the same organ, are not homogeneous, patient-to-patient variability is common, and heterogeneity can occur even in the same patient, so monotherapy with one actively targeted agent is unlikely to be uniformly effective. A particular category of fluorescent heptamethine cyanine-7 (Cy-7) dyes, here called

Topics: Benzothiazoles; Carbocyanines; Fluorescent Dyes; Humans; Neoplasms; Positron-Emission Tomography

Preferential accumulation of nanoparticles in a tumor is realized commonly by combined effects of active and passive targeting. However, passive targeting based on an enhanced permeation and retention (EPR) effect is not sufficient to observe clear tumor fluorescence images in most of the in vivo experiments using tumor-bearing mice. Herein, polyglycerol-functionalized nanodiamonds (ND-PG) conjugated with cyanine dye (Cy7) are synthesized and it is found that the resulting ND-PG-Cy7 is preferentially accumulated in the tumor, giving clear fluorescence in in vivo and ex vivo fluorescence images. One of the plausible reasons is the longer in vivo blood circulation time of ND-PG-Cy7 (half-life: 58 h determined by the pharmacokinetic analysis) than that of other nanoparticles (half-life: <20 h in most of the previous reports). In a typical example, the fluorescence intensity of tumors increases due to continuous tumor accumulation of ND-PG-Cy7, even more than one week postinjection. This may be owing to the stealth effect of PG that was reported previously, avoiding recognition and excretion by reticuloendothelial cells, which are abundant in liver and spleen. In fact, the fluorescence intensities from the liver and spleen is similar to those from other organs, while the tumor exhibits much stronger fluorescence in the ex vivo image.

Topics: Animals; Benzothiazoles; Carbocyanines; Fluorescence; Glycerol; Green Fluorescent Proteins; HeLa Cells; Humans; Hydrodynamics; Infrared Rays; Mice, Inbred BALB C; Mice, Nude; Nanodiamonds; Neoplasms; Optical Imaging; Polymers; Static Electricity; Time Factors

Molecular entities that localize in tumor tissue are clinically important for targeted delivery of diagnostic, imaging, and therapeutic reagents. Often these targeting entities are designed for specific receptors (e.g., EGFR or integrin receptors). However, there is a subset of cyanine-7 dyes that apparently localize in every type of solid tumor tissue (at least, no exceptions have been reported so far), and they persist there for several days. Consequently, these dyes can be used for near-IR optical imaging of tumors in animal studies, they can be conjugated with cytotoxic species to give experimental theranostics, and there is potential for expanding their use into the development of clinically useful derivatives. Data presented in the literature and in this work indicate that the half-lives of these compounds in serum at 37 °C is on the order of minutes to a few hours, so what accounts for the persistent fluorescence of these dyes in tumor tissue over periods of several days? Literature, solely based on tissue culture experiments featuring a particular receptor blocker, indicates that uptake of these dyes is mediated by the organic anion transporter proteins (OATPs). Data presented in this paper agrees with that conclusion for short-term uptake, but significantly expands understanding of the likely reasons for long-term uptake and persistent tumor localization in vivo.

Topics: Benzothiazoles; Carbocyanines; Cell Line, Tumor; Drug Delivery Systems; Fluorescent Dyes; Humans; Models, Molecular; Neoplasms; Optical Imaging; Organic Anion Transporters; Serum Albumin, Human

Nitroreductase (NTR) can be overexpressed in hypoxic tumors, thus the selective and efficient detection of NTR is of great importance. To date, although a few optical methods have been reported for the detection of NTR in solution, an effective optical probe for NTR monitoring in vivo is still lacking. Therefore, it is necessary to develop a near-infrared (NIR) fluorescent detection probe for NTR. In this study, five NIR cyanine dyes with fluorescence reporting structure decorated with different nitro aromatic groups, Cy7-1-5, have been designed and explored for possible rapid detection of NTR. Our experimental results presented that only a para-nitro benzoate group modified cyanine probe (Cy7-1) could serve as a rapid NIR fluorescence-enhanced probe for monitoring and bioimaging of NTR. The structure-function relationship has been revealed by theoretical study. The linker connecting the detecting and fluorescence reporting groups and the nitro group position is a key factor for the formation of hydrogen bonds and spatial structure match, inducing the NTR catalytic ability enhancement. The in vitro response and mechanism of the enzyme-catalyzed reduction of Cy7-1 have been investigated through kinetic optical studies and other methods. The results have indicated that an electro-withdrawing group induced electron-transfer process becomes blocked when Cy7-1 is catalytically reduced to Cy7-NH2 by NTR, which is manifested in enhanced fluorescence intensity during the detection process. Confocal fluorescence imaging of hypoxic A549 cells has confirmed the NTR detection ability of Cy7-1 at the cellular level. Importantly, Cy7-1 can detect tumor hypoxia in a murine hypoxic tumor model, showing a rapid and significant enhancement of its NIR fluorescence characteristics suitable for fluorescence bioimaging. This method may potentially be used for tumor hypoxia diagnosis.

Topics: Animals; Benzothiazoles; Carbocyanines; Cell Line, Tumor; Fluorescence; Fluorescent Dyes; Humans; Hypoxia; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Molecular Docking Simulation; Neoplasms; Nitroreductases; Optical Imaging; Whole Body Imaging

A highly selective and sensitive near-infrared (NIR) fluorescence probe (Cy-NO2) for imaging nitroreductase was developed and was successfully applied to investigating the relationship between epithelial-mesenchymal transitions (EMTs) in tumour progression and intracellular hypoxic level.

Topics: Benzothiazoles; Carbocyanines; Cell Hypoxia; Cell Survival; Fluorescent Dyes; Hep G2 Cells; Humans; Microscopy, Fluorescence; Microsomes, Liver; Neoplasms; Nitrogen Dioxide; Nitroreductases; Spectroscopy, Near-Infrared